Biaryls => anilines

Regioselectivity of the Birch reductive alkylation of polysubstituted biaryls is affected by the electronic nature of substituents on both aromatic rings. The electron-rich 3,5-dimethoxyphenyl moiety is selectively reduced and then alkylated, whereas phenols and aniline are not dearomatized under these conditions. Biaryls possessing a phenol moiety are alkylated on the second ring, provided that the acidic proton has been removed prior to the Li-NH3 reduction.300... 

For the preparation of biphenyl compounds with substituents in only one ring, it is usually advisable to employ a substituted aniline and couple with benzene rather than to use aniline and couple with a benzene derivative, since with benzene only a single biaryl compound is produced. Thus, 4-methylbiphenyl can be isolated readily in pure form from the reaction between diazotized p-toluidine and benzene, but not from the mixture of 2- and 4-methylbiphenyl formed from diazotized aniline and toluene. 

It is not possible to prepare biaryls containing a free carboxyl group directly by the diazo reaction. No biaryl is formed when (a) diazotized aniline and sodium benzoate, (b) diazotized anthranilic acid and aqueous sodium benzoate, or (c) diazotized anthranilic acid and benzene are used as components in the reaction.13 On the other hand, the reaction proceeds normally if methyl benzoate is used in reaction (a) or when methyl anthranilate replaces the anthranilic acid in (b) and in (c). The success of the diazohydroxide reaction appears to lie in the ability of the non-aqueous liquid to extract the reactive diazo compound from the aqueous layer.4 However, esters and nitriles can be prepared from esters of aromatic amino acids and cyanoanilines and also by coupling with esters of aromatic acids, and from the products the acids can be obtained by hydrolysis. By coupling N-nitrosoacetanilide with ethyl phthalate, ethyl 4-phenylphthalate (VIII) is formed in 37% yield. 

One of the side reactions is the formation of linear polyaryls, which may be considered to be formed by further reaction of the biaryl initially produced. From the high-boiling residue remaining after the removal of the biphenyl, formed from diazotized aniline, benzene, and alkali, p-terphenyl and quaterphenyl16 have been isolated and in the mixture formed in the preparation of 4-methylbiphenyl a hydrocarbon was found... 

Gomberg and Pemert4 recommended the use of the sodium diazotates for the preparation of biaryls from aniline and from p-toluidine and the normal diazo method for negatively substituted amines such as the bromo- and nitro-anilines. Grieve and Hey 7 found little difference in the yields of biaryls obtained by the two procedures when they coupled diazotized aniline with six different components benzene, toluene, m-xylene, chlorobenzene, nitrobenzene, and ethyl benzoate. Where it is applicable, this modification offers the advantage that the dropwise addition of alkali is eliminated. 

The reaction of pentafluoroiodobenzene with aromatic compounds such as anilines, pyrroles, indoles, imidazoles, aromatic ethers and phenols leads to aryl—aryl coupling477. The reactions proceed via pentafluorophenyl radicals which are generated by photoin-duced electron transfer (PET) and loss of iodide ion. Coupling between the pentafluorophenyl radical and the radical cation of the donor gives biaryl cations (138,139) which lose a proton. The reaction is illustrated for N, A-dimethylaniline (equation 125). 

When DABCO is replaced by brucine, enantioselective ortho-arylation of the aniline takes place at low temperature (—78 to —40°C) to afford the chiral biaryl with moderately good enantioselectivity (Equation (51)).68... 

Van der Eycken and co-workers [179] have reported a microwave-assisted A -MCR of an aniline, an alkyne and biaryl aldehyde to generate a small library of propargylamines 126 using CuBr as the catalyst. The resulting compounds 126 were isolated in good to excellent yields except when n-butylamine was used as amine counterpart and were further converted into Steganacin aza-analogs (Scheme 98). 

Many metalated aryl compounds are known to couple with aromatic compounds. Aniline derivatives react with ArPb(OAc)3, for example, to give the 2-arylani-line." Phenolic anions also react to form biaryls, with modest enantioselectivity in the presence of brucine." ... 

The mechanism of thallation appears to be complex, with electrophilic and electron-transfer mechanisms both taking place. Transient metalated aryl complexes can be formed that react with another aromatic compound. Aryl iodides reacted with benzene to form a biaryl in the presence of an iridium catalyst. Aniline derivatives reacted with TiCLj to give the para-homo coupling product (RaN-Ar-Ar-NRj). ... 

The protected hydrogen phosphonate of a 2 -deoxyadenosine tetracyclic analogue, (46) has been S5mthesised via the Stille biaryl coupling reaction of N-(rer/-butoxycarbonyl)-2-(trimethylstannyl)-aniline on a protected 6-chloro-7-deaza-7-iodopurine-2 -deoxyribose, followed by cyclisation. After subsequent deprotection and 5 -0-protection, the nucleoside analogue was treated with 2-chloro-4/7-l,3,2-benzodioxaphosphorin-4-one in the presence of pyridine. ... 

The palladium-catalyzed activation and subsequent functionalization of aryl hahdes has received increased attention in the last decade l The enormous synthetic possibilities are demonstrated in Scheme 1 by the synthesis of aromatic intermediates such as cinnamic acid derivatives, styrenes, biaryls, benzoic acids, benzonitriles, or anilines. 

From the synthetic point of view, aryllead(TV) compounds are efficient reagents for arylation of electron-rich aromatics such as polyalkylbenzenes, polyalkoxybenzenes, thiophenes, furans, phenols and anilines. Namely, the reaction of 4-methoxylead(IV) triacetate (484) with mesitylene (485) in the presence of trifluoroacetic acid resulted in formation of the biaryl 486 with a 84% yield [65], respectively. Scheme 33. 

In general it is not advisable to have the palladium-catalysed coupling reaction as last or penultimate step in view of the need to reduce palladium levels in the final product to below 10 ppm. Based on this reasoning, Taiwanese chemists patented an alternative route towards Lapatinib in which the furan ring is coupled to the quinazoline moiety before attachment of the substimted aniline (Scheme 23) [69]. Thus, coupling between the furfural-boronic acid 99 and aryl halide 103 catalysed by a catalyst prepared in situ from palladium acetate and one equivalent of tri-t-butylphosphine (2 mol%) gave the biaryl compound 104 in 98% HPLC yield. 

Three reviews have detailed progress in the formation of biaryl systems using metal-catalysed substitutions of carbon—hydrogen bonds. The preferential arylation at the para-position of phenol and aniline derivatives with diaryl iodonium salts has been achieved using copper catalysis. Under similar reaction conditions, a-arylacetamides are selectively arylated at the meta-position. A mechanistic study, including DFT calculations, suggests that the meta-selectivity in the copper-catalysed arylation of anilides derives from a Heck-like four-membered transition state involving a Cu(III)-phenyl species (47). 

This type of reaction is mainly restricted to heme peroxidases and it involves one-electron transfer processes with radical cations and radicals as intermediates (path 2). As a consequence, substrates are usually electron-rich (hetero)aromatics, which upon one-electron oxidation lead to resonance-stabilized radicals, which spontaneously undergo inter- or intramolecular coupling to form dimers or oligomers. This reaction is commonly denoted as the classical peroxidase activity, since it was the first type of peroxidase-reaction discovered. Examples of such reactions are shown in Scheme 2.176. Oxidation of phenols (e.g., guaiacol, resorcin) and anilines (e.g., aniline, < -dianisidine) leads to the formation of oligomers and polymers under mild conditions [1315-1317], In certain cases, dimers (e.g., aldoximes [1318], biaryls [1319]) have been obtained. 

Examples of organic molecnles [75] nsed as reducing agents inclnde ascorbic acid, which has been snccessfully employed as a radical initiator in a C—H arylation of benzene with anilines 107 to afford the biaryl componnds 108 atrt [76] (Eq. 9.21) ... 

Kaboudin B, Mostafalu R, Yokomatsu T (2013) FejO nanoparticle-supported Cu(ll)-p-cyclodextrin complex as a magnetically recoverable and reusable catalyst for the synthesis of symmetrical biaryls and 1,2,3-triazoles from aryl boronic acids. Green Chem 15 2266-2274 Roy S, Chatteijee T, Islam SM (2013) Polymer anchored Cu(II) complex an efficient and recyclable catalytic system for the one-pot synthesis of 1,4-disubstituted 1,2,3-triazoles starting from anilines in water. Green Chem 15 2532-2539... 

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